Podcast 116 – the tPA for Ischemic Stroke Debate

The debate seemed relevant because ACEP, a major US emergency medicine organization, released clinical guidelines markedly increasing stress on thrombolysing stroke. These clinical guidelines were sent back by ACEP's council for further commentary and assessment, a move unprecedented in the history of the organization.

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Scott Weingart. Podcast 116 – the tPA for Ischemic Stroke Debate. EMCrit Blog. Published on January 27, 2014. Accessed on January 21st 2019. Available at [http://emcrit.org/emcrit/tpa-for-ischemic-stroke-debate/ ].

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Unless otherwise noted at the top of the post, the speaker(s) and related parties have no relevant financial disclosures.

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Mike

Love the debate, but it confuses me even more. I liked at the end when Scott asked about what both would tell patients, but neither clarified what data (i.e. risk and benefit percentage/NNTs) to present to the patient/family to obtain true informed consent. I’ve tried the “it’s complicated and controversial with a few studies showing benefit in three months, a bunch showing no benefit, and some showing harm due to bleeding in the brain. The risks and benefits depend on which studies we believe” but patients and/or families get frustrated and ask about the chances of helping or harming as if I can give them firm numbers. I tell them that I have my own opinions about receiving or giving it to my family but don’t want to influence them too much. How do you guys handle these situations?

What's Your Job?

ED Physician

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1 year ago

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Phil G

Nice debate! As always nice podcast! 2 major questions: 1. tPA (Tissue plasminogen activator) is an enzyme-like protein that is supposed to accelerate the conversion of plasminogen to plasmin which should lead to a fibrinolysis and blood clot breakdown. From these basic hemostatic or coagulation considerations, the level of fibrinogen should dramatically drop after tPA, assessing the good quality of thrombolysis. However, in various studies the level of fibrinogen before and after is not reported. Why the hell is that? So simple to assess the effectiveness of this therapy. Patients may exhibit different inflammation profiles, one with high basal fibrinogen levels, so the amount of intravenous-tPA required to induce a significant fibrinolysis may be insufficient. 2. Considering cardiac output, how much blood flow would represent the distal part of an MCA for exemple ? 2 to 3% or less of total cardiac output? Moreover, what about a patient with severe carotid stenosis? the superimposed reduced blood flow would increase the failure of this treatment. In other words, is the patient sufficiently “thrombolysed” to reach the initial target? Do we have tool to assess that? In massive pulmonary embolism (proximal), half or all of the cardiac output is passing through pulmonary… Read more »

Higher doses of tPA have been used but the Cochrane collaborative found that dose (as well as agent) made no difference. This is important because the NINDS and ECASS III supporters make a point of saying that the higher doses of alteplast in other studies was part of the reason those studies had poorer outcomes.

Overall, the pathophysiology of stroke is different and perhaps we just don’t understand it as well as we think we do.

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4 years ago

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donald zweig

so although it was fun i would have liked to hear Swami ask andy how he explains and rationalizes all the data mining and the gross inconsistencies in Ics3 with the time window helping for 4.5-6 but hurting for 3-4.5 and the FACT that we need to better define who and when people will benefit.

Also, how does Andy explain the lack of benefit at 24 hours if the clot is breaking up and every time the pt improves in the first few hours we declare it a success.

We didn’t get too much into IST-3 because the ACEP clinical committee sort of understood the limitations of this study and didn’t really use it to back up their recommendations. I did bring it up briefly as a good defense of the fact that time probably doesn’t matter nearly as much as NINDS would make us believe.

Completely agree with you on the second part and I think Andy would as well. We shouldn’t be celebrating an improvement at 24 hours as a success of tPA because no study has ever shown that and in fact NINDS clearly shows that those improvements aren’t due to the drug.

I would not base any conclusions on IST-3, not on the safety on large bleeds nor on time-to-drug. If you are going to give tPA, give it as quickly as possible. The trial was flawed from the get-go, all we can say is it wasted a lot of people’s time.

First, I am quite the fan of emcrit, emrap, resus.me and consorts – I admire your rebel-like ability to question the most basic assumptions in emergency medicine, even it it is tPA. I consider myself an emergency neurologist and do all of the daytime thrombolysis assessments (i.e. strokes in the first few hours) of our hospital myself. This amounts to about 200 tPA for stroke (of our ~400) yearly, so that I have overseen about 600 tPA patients personally and about 1000 in total on my stroke unit. Let me also add that we do proximal artery occlusions with good collateralization endovascularly (about 100/a). Here are my few cents: you discuss a 20 year old study. Time has moved on, you should as well. We oversee countless (> 50,000) applications of tPA in registries and do outcome assessment on our own patients as well. Our 24h bleeding rate is 1,2% in the last year (this is non-proximal artery occlusions, the others are done endovascularly + bridging or not at all). But that’s not the whole story. Now that we have done enough tPA we do understand who is in danger of bleeding (not only in the first 24h but also… Read more »

Thank you for your thoughtful comments. I’ll start by saying that for this particular debate, NINDS is not irrelevant. In fact, it is the heart of the debate as the debate centers on the ACEP clinical policy which centers on the level A recommendation for the use of tPA in stroke < 3 hours based on NINDS. Registry data is nice but it's not the quality of data upon which a Level A recommendation should be based. We focus on NINDS because it highlights many of the issues we see with research. A single study of 300 patients showing a benefit should not lead to a marked change in treatment. It should be followed up by repeat RCTs (preferably blinded) to prove the benefit. This is particularly important as a cautionary tale for future research and therapeutics. Clot retrieval devices don't work. Three papers in the NEJM showed this last year. In spite of this, people still use the devices (the authors even stated that they should only be used in studies until there's proven benefit). Also, as soon as a single study shows benefit, the device companies will start pushing for wide acceptance and use of this modality. We… Read more »

As folks know, I am in a state of equipoise on this topic. I believe there is a group that will benefit and I believe we have not figured out the parameters of that group yet, so the question then is do you want to overtreat or undertreat–I can see compelling arguments for both sides.

I hope the ANZICS folks or similar will do a real RCT and settle this once and for all.

>>What about stroke mimics? I don’t care – they don’t bleed.
What I will say in response to Felix’s comments is that unfortunately these folks can have intracranial bleeding. It is not a free ride. Perhaps the best evidence is the bleed rate from PEITHOS ( a large pulmonary embolism RCT). 10x higher intracranial bleeding rate for patients with tpa compared to heparin alone. These patients did not have the risks you mentioned, but they bled.

This is fun, really. 1. Proving tpa? There are two conflicting perspectives – a) politics aka guidelines b) medical. If you forget about the fact that you don’t like the NINDS study and try to find a way to make tpa use safe. Let me think… We should do a registry. Okay. Did that. Even got plenty of subgroups to dissect (such as mimics). Or we should try to increase the time window that we can use the drug, so that it looks safer in the first hours. Okay. Did that – is dangerous, because later strokes are bigger, so more NNT (not more dying though). We should then do a study that extends it to the boundaries, say, old people, with lots of contraindications. Yup. Still they don’t bleed too much. Politically speaking, assume tpa works, how would you now (given that it is the standard treatment) show that it does in the standard patient? You can’t. So you can only claim that it doesn’t work. But you cannot prove it, because you would withhold a standard treatment. So let us move on and just use it, even if you doubt the evidence. 2. Stent retrievers. You are right.… Read more »

I think there are some weaknesses in the pathophysiologic explanation that time is brain in comparison to time is heart. In an MI, you lyse (or stent) and there is a rapid response of the cardiac muscle to resuming flow. This doesn’t happen in CVA. If it did, shouldn’t we see a benefit at 24 hours (or sooner)? In the MR RESCUE trial, revascularization was 67% in the endovascular treatment group but this didn’t translate to improved outcomes. Revascularization doesn’t necessarily seem to equal good outcomes as it does in MI.

You are right, but that exactly proves the point of time is brain. It does not suffice to open up the artery. If blood comes the ischemic tissue suffers first, quite a lot sometimes, depending on the amount of damage through ischemia and reperfusion (which does harm at first). It swells, convulses, might even bleed. The more damage there was the longer it takes to recover – this takes days in mice. In patients it can take up to weeks (as a good model take reperfusion syndrome after carotid endarterectomy for filiform stensoses with bad collaterals, which sometimes lasts for months).
What we can do now is learn whom to treat aggressively and whom not. And there is more than the data from NINDS to mine.
With regard to the bleeding mimics: you can’t take the cardiac studies as a reference for the baseline bleeding risk, because there is the huge difference of an initial CT in stroke mimics.

In response to: “In an MI, you lyse (or stent) and there is a rapid response of the cardiac muscle to resuming flow.” This is not true. After complete ischemia for > 1 hour, it takes days to many weeks to recover cardiac function, called “myocardial stunning.” Similarly, ischemic brain takes a long time to recover (if it does).

Also, one writer was skeptical that tPA could have any effect in a tiny, occluded MCA. But it is clearly effective in tiny, occluded, coronary arteries.

It does make sense that tPA would not work in embolic, as opposed to thrombotic, stroke, as these may be well organized thrombi.

Wonderful debate that was fascinating to listen to. This does remind me in several ways of political debates – in which whether one is Republican/Conservative or Democratic – I’ve found it near impossible to sway anyone from their beliefs that usually are firmly fixed. So realizing poor Scott is “stuck” in equipoise (for obvious reasons given that his Chair is one of the debaters …. ) – I have to support Anand Swaminathan’s point that NINDS is not irrelevant – because it was based on NINDS data that the Level A recommendation was made. I thought Anand very effectively pointed out the problematic nature of NINDS data – such that I fail to understand Andy Jagoda’s argument that we need to “accept” this Level A recommendation when the primary study on which the recommendation was based is so problematic (ie, clearly NOT in my opinion worthy of a Level A recommendation). It’s obvious that we won’t reach consensus on this issue – but I thought the theoretical issue brought up in the Q&A at the end of the Podcast about, “What if this was only a Level B or C Recommendation” made a whole lot more sense – because the… Read more »

I keep hearing from some pro-tPA folks that the NNT for thrombolysis is 2. Even in the optimistic views I had not seen any analysis suggesting it’s less than 6 or 7; anyone have any idea what they’re referring to?

Even the most optomistic numbers don’t show this but I’ve heard some stroke specialists give an NNT of 3 or 4 so 2 isn’t out there from their perspecitve. This idea must be based on data dredging and/or misinterpretation of the data. There is no evidence from any study that gives you that number.

I found what Jagoda was saying to be extremely troubling. He kind of boils it down to: regardless of what you think about the data, tPA for stroke is a level 1 recommendation of ACEP and multiple professional societies, is now the standard of care, and so the debate is over. Nevermind how that came to be or what you think the data truly show or don’t show. The science is settled. And if you as a clinician have concluded that this therapy is neither proven to be safe or effective and don’t use it, ‘you better document really well.’ Implied: because you are going to get sued. And it sounds like he would be willing to jump right up on the stand and testify against you. He is making a common logical mistake that most of us are familiar with: the appeal to authority. This is the policy of ACEP and everyone else, ergo the therapy must be effective. What is also troubling about listening to Jagoda is that he has been front and center in making tPA for stroke from the earliest days, serving on committees of policy makers. He is heavily invested in this, has been pushing… Read more »

[…] later, this continues to be a hot button topic in EM. You can see more on the tPA debate here on ERCrit Episode as well as at many other FOAMed resources. This last year, ACEP updated their clinical policy […]

[…] in its inconsistency. A full discussion of the risks and benefits is beyond this post but check out my pro-con debate with Andy Jagoda on the EMCrit podcast back in January of 2014 and the EM Lyceum blog on the topic from August […]

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4 years ago

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Jean Marc Benoit

Coming to this a little late, but then again we only had our official “strokologist” tele-stroke speech last week. Unlike Dr Jagoda, our regional neurologist outright stated that “if you don’t use it, you will get sued.” Interestingly, he also cited a number needed to treat of 2. Tpa clinician-lobbyists appear to share an interesting template of a) appeals to authority, b) legal threat, and c) rather robust claims of efficacy (NNT2!).

Lest this give way to despair over the death of science and the rise of eminence-based medicine, we can take heart in the great discovery which lies hidden within this rather unusual scientific-political debate:

[…] the details. You might just be surprised. Some of our favorite sites are REBEL EM, The SGEM, EmCrit, FOAMcast, and First10EM. Health News Review also did a nice piece directly related to the New […]